There are more than 750,000 cases of severe sepsis and septic shock in the US each year. Most patients who present with sepsis receive their initial care in the emergency department. In 2001, there was a landmark study by Rivers et al that reported that among patients with severe sepsis or septic shock mortality was significantly lower among those who received a 6 hour protocol of Early Goal-Directed Therapy (EGDT) (i.e. 30.5% vs 46.5%). The premise of EGDT was that “usual care” lacked aggressive, timely assessment and treatment. The EGDT protocol used central venous catheterization (CVC) to monitor central venous pressure (CVP) and central venous oxygen saturation (SCVO2) to guide the use of intravenous fluids (IVFs), vasopressors, packed red blood cell (PRBC) transfusions, and dobutamine in order to achieve pre-specified physiological targets. Since the publication of this landmark article, physicians have become more aggressive in the management of sepsis which raises the question of whether all elements of the protocol are still necessary.

What are the newest studies evaluating sepsis management?

The ProCESS Trial

Multicenter, Randomized Control Trial of 1341 patients with septic shock (31 EDs in the US) randomized to one of 3 arms:

Protocol Based EGDT

Protocol-Based Standard Therapy without use of CVC, administration of inotropes, or blood transfusions

Usual Care

Primary Endpoint: 60 day in-hospital mortality

Results:

92 deaths in EGDT group (21.0%)

81 deaths in Protocol Based Standard Therapy (18.2%)

86 deaths in Usual Care (18.9%)

No statistical difference in 90 day and 1 year mortality

Categories

EGDT

Protocolized Care

Usual Care

IVFs (Over 1st 6 hours)

5 L

5.5L

4.4L

Vasopressors

54%

52%

44%

CVC

93%

56%

57%

Dobutamine

8%

1%

1%

Packed Red Blood Cells

14%

8%

8%

Limitations:

Cannot be sure that all elements critical to the success of the Rivers et al. protocol were adhered to 100% of the time in the EGDT arm

Only patients who were recognized early as septic shock were enrolled in this study (i.e. Early IVF with refractory hypotension and early antibiotics then randomized into one of three arms), not delayed presentations of septic shock

This study was performed in large tertiary care centers in the US, so it is not clear how this study would translate into other settings (i.e. Smaller, rural, community EDs)

Study Conclusion: Protocol-based resuscitation of patients with septic shock does not improve 60 day mortality

The ARISE Trial

What they did:

Prospective, Multicenter, Randomized Control Trial of 1600 patients presenting to an ED with early septic shock

Low APACHE scores (15.4 in EGDT vs 15.8 in Usual Care) compared to the ProCESS Trial (20.8 in EGDT, 20.6 in Protocol Based Care, and 20.7 in Usual Care) but most patients had lactate levels ≥4 in both groups (46.0% in EGDT vs 46.5% in Usual Care) which means this was still a sick patient population

Study Conclusion: In patients presenting to the Emergency Department with Early Septic Shock, EGDT did not reduce all-cause mortality at 90 days

My Thoughts on These Studies:

The ProCESS Trial:

If patients in septic shock are identified early, given IVF early, and antibiotics early, then the CVC and central readings should not matter in the care of septic shock patients

This study did not create a clear, superior method in management of septic shock patients, but did make it clear that no one resuscitative pathway is bad or better. This gives various sites flexibility in management after early recognition, early IVFs, and early antibiotics.

The cohort of patients in this study is different than the cohort of patients in the 2001 Rivers et al study. Although Vital Signs and APACHE scores were similar between the two studies, the mortality rates were significantly different (i.e. EGDT mortality decreased from 47 –> 31% [NNT = 6] in the 2001 Rivers et al study and in the ProCESS trial mortality rates were 21% in EGDT, 18.2% in protocolized care, and 18.9% in usual care arms)

The 2001 Rivers et al study has changed how we manage sepsis (i.e. We are more aggressive in identifying these patients, and our “usual care” has changed to early identification, early IVFs and early antibiotics), which may explain why we have lower mortality rates now compared to the 2001 Rivers et al study

The ARISE Trial

This trial took place in tertiary and non-tertiary metropolitan and rural EDs, which allows for more generalizability of results

This trial was not a blinded study, due to the requirements of EGDT. The authors stated that they tried to minimize bias through “central randomization, concealment of study-group assignments before randomization to avoid selection bias and the use of a robust primary outcome that would not be subject to observer bias.“

Again the mortality rate of this study was lower than the 2001 Rivers et al study (i.e. EGDT mortality decreased from 47 –> 31% [NNT = 6] in the 2001 Rivers et al study and in the ARISE trial mortality rates were 18.6% in EGDT and 18.8% in usual care arms)

Clinical Take Home Message:

Simply put, in septic shock, we need to be AGGRESSIVE in our care EARLY. If patients are identified EARLY, given IVF EARLY, and antibiotics EARLY, again the key being EARLY, then the pathway used afterwards (i.e EGDT, Protocolized, or “usual care”) is less important in management and resuscitation.

One of the challenges I see with just about any sepsis protocol is the fluid bolus. It seems that the delivery of 30mL/kg is something that is often times the crux. In my ED we’ve had problems with patients not getting the full initial bolus, but as it turns out this is common. Why? Nurses are afraid of fluid overloading or large boluses in the absence of labs– well at least that’s what Ive found surveying my peers. As we work on education and a new protocol to improve our outcomes, one of the suggestions was using the Level I for rapidly infuse the initial bolus. Now I haven’t really seen to much mention of this and I’m wondering if anyone is doing it, pre labs lactate, CBC… Looking for some feedback. Thanks.

Hello Kate,
I too have found many physicians fearful of fluid boluses of 30cc/kg. I have not seen any literature on the rapid infusers for this but I do have some evidence that more fluids is not necessarily harmful:

Patients enrolled in SEPSISPAM Trial and ProCESS Trials were fairly similar with similar pre-enrollment fluid administration and patients in ProCESS trial even being a bit sicker (i.e. Lower MAP, Higher Initial Lactate Levels)